PhD project: Development and preclinical evaluation of diagnostic and therapeutic radiopharmaceuticals for pancreatic cancer

Using dedicated radiopharmaceuticals, nuclear medicine significantly contributes to all stages of cancer patient care, including early detection, diagnosis, therapy monitoring and treatment.  Apart from external high energy X-ray beam therapy, Targeted RadioNuclide Therapy (TRNT) is another approach to deliver radiation to cancer cells. In TRNT, the therapeutic radiopharmaceutical is distributed within the body by the vascular system and allows targeted irradiation of a primary tumor and all its metastases, resulting insubstantially less collateral damage to normal tissues as compared to external radiotherapy. TRNT represents an established, evidence-based treatment modality and its role has been enforced by the excellent results obtained in the randomized, controlled NETTER-1 and VISION trial using the radiopharmaceuticals 177Lu-DOTATATE and 177Lu-PSMA-617, respectively. 

The overall objective of this project is to develop and evaluate therapeutic radiopharmaceuticals for the treatment of pancreatic cancer. Our aim is to create an innovative pipeline of cancer-specific theranostics (therapeutic: ther; diagnostic: anostics) that will improve the treatment options for NET patients who are refractory to 177Lu-DOTATATE therapy, or have reached the maximum prescribed cycles of 177Lu-DOTATATE therapy and for PDAC patients with otherwise limited or non-existing treatment alternatives. 

We will realize this by using two different classes of vector molecules that have completely different modes of binding and we will combine them with potent radioactive payloads such as the alpha-emitter 213Bi and the promising radionuclide 161Tb. We hypothesize that this approach will lead to more localized and effective destruction of cancer and cancer-supporting cells compared to standard β--emitters (e.g. 177Lu), and this in both hypoxic as well as in normoxic tumor cell environments. To produce the diagnostic partners, we will use the well-established Al18F-method. As vector molecule we will use 1) Somatostatin analogues, including agonists and antagonists targeting SSTR2 which is overexpressed on most pancreatic NETs, and compounds targeting fibroblast activating protein that is abundantly present in the tumor microenvironment of PDAC. 

The project will involve, but is not limited to, organic synthesis, various analytical techniques (NMR, HPLC, HRMS, …), radiochemistry with diagnostic and therapeutic radionuclides, in vitro cell work, in vivo imaging studies in small animals, therapeutic efficacy studies in tumor models and preparation for clinical translation in collaboration with Nuclear Medicine and Molecular Imaging (NMMI) unit (Prof. C. Deroose).